N-Acylethanolamine-Hydrolyzing Acid Amidase Inhibition, but Not Fatty Acid Amide Hydrolase Inhibition, Prevents the Development of Experimental Autoimmune Encephalomyelitis in Mice.

Abstract

N-acylethanolamines (NAEs) are endogenous bioactive lipids reported to exert anti-inflammatory and neuroprotective effects mediated by cannabinoid receptors and peroxisome proliferator-activated receptors (PPARs), among others. Therefore, interfering with NAE signaling could be a promising strategy to decrease inflammation in neurological disorders such as multiple sclerosis (MS). Fatty acid amide hydrolase (FAAH) and N-acylethanolamine-hydrolyzing acid amidase (NAAA) are key modulators of NAE levels. This study aims to investigate and compare the effect of NAAA inhibition, FAAH inhibition, and dual inhibition of both enzymes in a mouse model of MS, namely the experimental autoimmune encephalomyelitis (EAE). Our data show that NAAA inhibition strongly decreased the hallmarks of the pathology. Interestingly, FAAH inhibition was less efficient in decreasing inflammatory hallmarks despite the increased NAE levels. Moreover, the inhibition of both NAAA and FAAH, using a dual-inhibitor or the co-administration of NAAA and FAAH inhibitors, did not show an added value compared to NAAA inhibition. Furthermore, our data suggest an important role of decreased activation of astrocytes and microglia in the effects of NAAA inhibition on EAE, while NAAA inhibition did not affect T cell recall. This work highlights the beneficial effects of NAAA inhibition in the context of central nervous system inflammation and suggests that the simultaneous inhibition of NAAA and FAAH has no additional beneficial effect in EAE.

• Authors: Pauline Bottemanne, Owein Guillemot-Legris, Adrien Paquot, Julien Masquelier, Michael Malamas, Alexandros Makriyannis, Mireille Alhouayek, Giulio G Muccioli
• Journal: Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics (Neurotherapeutics) Vol. 18 Issue 3 Pg. 1815-1833 (07 2021) ISSN: 1878-7479 [Electronic] United States
• PMID: 34235639 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2021. The American Society for Experimental NeuroTherapeutics, Inc.

Chemical References

• Enzyme Inhibitors
• PF 3845
• Piperidines
• Pyridines
• Amidohydrolases
• NAAA protein, mouse
• fatty-acid amide hydrolase

Topics

• Amidohydrolases (antagonists & inhibitors, metabolism)
• Animals
• Coculture Techniques
• Encephalomyelitis, Autoimmune, Experimental (enzymology, prevention & control)
• Enzyme Inhibitors (pharmacology, therapeutic use)
• Female
• Mice
• Mice, Inbred C57BL
• Piperidines (pharmacology, therapeutic use)
• Pyridines (pharmacology, therapeutic use)